dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness and convulsions [see adverse reactions (6.2) ] . always have cardiopulmonary resuscitation personnel and equipment readily available prior to optison administration and monitor all patients for acute reactions. 5.2 hypersensitivity reactions serious anaphylactic reactions have been observed during or shortly following perflutren-containing microsphere administration including: shock, hypersensitivity, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema have occurred in patients with no prior exposure to perflutren-containing microsphere products. always have cardiopulmonary resuscitation personnel and equipment readily available prior to optison administration and monitor all patients for hypersensitivity reactions [see adverse reactions (6.2) ] . 5.3 systemic embolization when administering optison to patients with a cardiac shunt, microspheres can bypass filtering of the lung and enter the arterial circulation. assess patients with shunts for embolic phenomena following optison administration. optison is only for intravenous administration; do not administer optison by intra-arterial injection [see dosage and administration (2.3) ] . 5.4 ventricular arrhythmia related to high mechanical index high ultrasound mechanical index values may cause microsphere rupture and lead to ventricular arrhythmias. additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. optison is not recommended for use at mechanical indices greater than 0.8. 5.5 transmissible infectious agents this product contains albumin, a derivative of human blood. based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral disease. a theoretical risk for transmission of creutzfeldt-jakob disease (cjd) also is considered extremely remote. no cases of transmission of viral disease or cjd have ever been identified for albumin.

urther contrast enhancement as needed. the maximum total dose should not exceed 5 ml in any 10 minute period. the maximum total dose should not exceed 8.7 ml in any one patient study. 2.2 preparation instructions do not use if the container has been damaged, the protective seal and/or rubber cap have been entered, or the upper white layer is absent (may indicate the microspheres have been damaged and may result in poor or no echo contrast). invert the optison vial and gently rotate to resuspend the microspheres. this process will allow the product to come to room temperature (20° to 25°c or 68° to 77°f) before use. inspect the vial for complete resuspension. do not use if the suspension appears to be clear rather than opaque and milky-white. vent the optison vial with a sterile vent spike or with a sterile 18 gauge needle before withdrawing the optison suspension into the injection syringe. do not inject air into the vial. use the product within one minute of suspension. if one minute is exceeded, resuspend by inverting and gently rotating the microsoheres in the syringe. failure to adequately resuspend optison may cause inadequate delivery of the microspheres, and may result in inadequate contrast. 2.3 administration instructions inspect visually for particulate matter and discoloration prior to administration, whenever supension and container permit. do not inject if the suspension is not opaque, milky-white, and absent particulate matter. inject through a 20-gauge or larger angiocatheter into a peripheral vein at a rate not exceeding 1 ml per second. suggested methods of administration include: a short extension tubing, heparin lock, or intravenous line, all with a 3-way stopcock. administer intravenously; do not administer optison by intra-arterial injection [see warnings and precautions (5.3) ] . do not aspirate blood back into the optison containing syringe before administration; this may promote the formation of a blood clot within the syringe. for short extension tubing or heparin lock: fill one syringe with 0.9% sodium chloride injection, usp, and flush the line for patency before and after the injection of optison. for a continuous intravenous line: open an intravenous line with 0.9% sodium chloride injection, usp (or 5% dextrose injection, usp) at a slow infusion rate to maintain vascular patency. flush the line immediately after injection of optison. do not use the single-patient use vial for more than one patient. discard unused product.

%) hispanic, and 4 (1.4%) other racial or ethnic groups. in these patients, 47 (16.8%) reported at least one adverse reaction. of these one reaction was serious and required treatment with antihistamines for hypersensitivity manifestations of dizziness, nausea, flushing and temperature elevation. deaths were not reported during the clinical studies. of the reported adverse reactions following the use of optison the most frequently reported were headache (5.4%), nausea and/or vomiting (4.3%), warm sensation or flushing (3.6%), and dizziness (2.5%). the most common adverse reactions observed in clinical studies of optison are given in table 1. table 1 selected adverse reactions reported in ≥ 0.5% of the subjects who received optison™ in controlled clinical studies patients are counted separately within each body system. the body system is reported if the aggregate is ≥ 0.5%. details are not shown if the subsystem is not ≥ 0.5%. no. of patients exposed to optison 279 no. of patients reporting on adverse reactions 47 (16.8%) body as a whole 38 (13.6%) headache 15 (5.4%) warm sensation/flushing 10 (3.6%) chills/fever 4 (1.4%) flu-like symptoms 3 (1.1%) malaise/weakness/fatigue 3 (1.1%) cardiovascular system 12 (4.3%) dizziness 7 (2.5%) chest pain 3 (1.1%) digestive system 12 (4.3%) nausea and/or vomiting 12 (4.3%) nervous system 3 (1.1%) respiratory system 5 (1.8%) dyspnea 3 (1.1%) skin & appendages 11 (3.9%) injection site discomfort 3 (1.1%) erythema 2 (0.7%) special senses 9 (3.2%) altered taste 5 (1.8%) adverse reactions reported in < 0.5% of subjects who received optison included: arthralgia, back pain, body or muscle aches, induration, urticaria, dry mouth, palpitations, paresthesia, photophobia, premature ventricular contraction, pruritus, rash, irritableness, hypersensitivity, tinnitus, tremor, visual blurring, wheezing, oxygen saturation decline due to coughing, discoloration at the injection site, and burning sensation in the eyes. 6.2 postmarketing experience in a prospective, post-marketing safety surveillance study of optison used in routine clinical practice, a total of 1039 subjects received optison. of these patients, 648 (62.4%) were male and 391 (37.6%) were female with average age of 59.9 years (min, max: 20, 97). the racial distributions were 864 (83.2%) white, 141 (13.6%) black, 18 (1.7%) asian, and 16 (1.5%) other racial or ethnic groups. overall, 175 patients (16.8%) reported at least one adverse event. no serious adverse reactions, including deaths, were reported in this study. the following adverse reactions have been identified during the postmarketing use of perflutren-containing microspheres. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. cardiac arrests, including fatalities, and other serious adverse reactions were uncommonly reported. most of these reactions included cardiopulmonary symptoms and signs such as cardiac arrest, hypotension, supraventricular and ventricular arrhythmias, respiratory distress or decreased oxygenation. reports also identified neurologic reactions (loss of consciousness or convulsions). hypersensitivity anaphylaxis, with manifestations that may include death, shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema.

no significant findings attributable solely to a direct effect on the fetus were detected in the studies. 8.2 lactation there are no data on the presence of perflutren protein-type a microspheres in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for optison and any potential adverse effects on the breastfed infant from optison or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use of the total number of subjects in a clinical study of optison, 35% were 65 and over, while 14% were 75 and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

butable solely to a direct effect on the fetus were detected in the studies.

nce of the microspheres. the pharmacokinetics of the intact microspheres of optison in humans are unknown. distribution the binding of perflutren to plasma proteins and its partitioning into blood cells are unknown. however, perflutren protein binding is expected to be minimal due to the low partition coefficient of the gas in blood. elimination following intravenous injection, perflutren is cleared with a pulmonary elimination half-life of 1.3 ± 0.69 minutes (mean ± sd). metabolism perflutren is a stable gas that is not metabolized. the human albumin component of the microsphere is expected to be handled by the normal metabolic routes. excretion perflutren is eliminated through the lungs within 10 minutes. the mean ± sd recovery was 96% ± 23%. the perflutren concentration in expired air peaked approximately 30-40 seconds after administration.

expired air peaked approximately 30-40 seconds after administration.

an 20% or with new york heart association class iv heart failure were not included in the studies. after non-contrast imaging, optison was administered in increasing increments as 4 doses (0.2, 0.5, 3.0 and 5 ml) with at least ten minutes between each dose. ultrasound settings were optimized for the baseline (non-contrast) apical four-chamber view and remained unchanged for the contrast imaging. static echocardiographic images and video-tape segments were interpreted by a reader who was blinded to the patient's clinical history and to the dose of optison. left ventricular endocardial border delineation and left ventricular opacification, were assessed before and after optison administration by the measurement of visualized endocardial border length and ventricular opacification. in comparison to non-contrast ultrasound, optison significantly increased the length of endocardial border that could be visualized both at end-systole and end-diastole (see table 3 ). in these patients there was a trend towards less visualization in women. optison increased left ventricular opacification (peak intensity) in the mid-chamber and apical views (see table 4 ). the imaging effects of optison on endocardial border delineation and left ventricular opacification were similar at doses between 0.5 ml and 5 ml and were also similar among patients with or without pulmonary disease and dilated cardiomyopathy. table 3 left ventricular endocardial border length before and after optison the differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images. , an intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results. length at end-systole (cm) length at end-diastole (cm) optison dose n mean ± s.d. n mean study a (n=101) 0 ml (baseline) 87 7.7 ± 3.0 86 9.3 ± 3.4 0.5 ml 86 12.0 ± 4.9 91 15.8 ± 5.1 study b (n=102) 0 ml (baseline) 89 8.1 ± 3.4 89 9.6 ± 3.7 0.5 ml 95 12.4 ± 4.9 97 16.4 ± 4.6 table 4 intensity of left ventricular opacification intensity measured by videodensitometry in arbitrary gray scale units (0-255). before and after optison™ the differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images. , an intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results. mid-chamber apex intensity at end-diastole intensity at end-systole intensity at end-diastole intensity at end-systole optison dose n mean ± s.d. n mean ± s.d. n mean ± s.d. n mean ± s.d. study a (n = 101) 0 ml (baseline) 91 39.5 ± 16.9 91 40.0 ± 18.1 91 46.7 ± 19.7 91 46.9 ± 20.1 0.5 ml 91 57.3 ± 26.8 90 57.4 ± 26.7 91 67.0 ± 30.1 90 64.1 ± 30.2 study b (n = 102) 0 ml (baseline) 95 40.4 ± 17.4 95 40.9 ± 17.5 95 43.7 ± 19.9 95 45.0 ± 19.6 0.5 ml 97 53.3 ± 20.7 96 53.6 ± 21.0 97 64.4 ± 25.3 96 61.6 ± 26.7 14.2 pulmonary hemodynamic effects the effect of optison on pulmonary hemodynamics was studied in a prospective, open-label study of 30 patients scheduled for pulmonary artery catheterization, including 19 with an elevated baseline pulmonary arterial systolic pressure (pasp) (>35 mmhg) and 11 with a normal pasp (≤35 mmhg). systemic hemodynamic parameters and ecgs were also evaluated. no clinically important pulmonary hemodynamic, systemic hemodynamic, or ecg changes were observed. this study did not assess the effect of optison on visualization of cardiac or pulmonary structures.